Antagonism of the Serotonin (5-HT)-2 Receptor and Insulin Sensitivity: Implications for Atypical Antipsychotics

Gilles, Maria; Wilke, Annette; Kopf, Daniel; Nonell, Annemarie; Lehnert, Hendrik; Deuschle, Michael

doi:10.1097/01.psy.0000174994.91245.34

Cited by 46 publications

(28 citation statements)

References 23 publications

(23 reference statements)

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“…5). These findings may well help explain the contradictory discoveries about why ketanserin impairs insulin sensitivity, yet sarpogrelate improves the insulin sensitivity and glucose metabolism (Takishita et al, 2004;Gilles et al, 2005).…”

Section: Discussionmentioning

confidence: 89%

Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes

Hosaka

Harada

et al. 2013

Molecular and Cellular Endocrinology

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Section: Discussionmentioning

confidence: 89%

Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes

Hosaka

Harada

et al. 2013

Molecular and Cellular Endocrinology

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“…Work in healthy volunteers has since shown that 5-HT 2 antagonists can significantly decrease insulin sensitivity compared with placebo (P = 0.047), an effect possibly mediated by the suppression of 5-HT 2A receptor-mediated glucose uptake in skeletal muscle. 86 It should be noted, however, that most atypical antipsychotics have stronger antagonistic effects at 5-HT 2A and 5-HT 2C than at 5-HT 1A , 85 and that 5-HT 2C antagonism is most closely correlated with an increased risk of diabetes and weight gain. 53 Consistent with this notion, 5-HT 2C knockout mice develop insulin resistance and impaired glucose tolerance and experience severe weight gain.…”

Section: Diabetes 62mentioning

confidence: 99%

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

2007

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Atypical antipsychotic drugs offer several notable benefits over typical antipsychotics, including greater improvement in negative symptoms, cognitive function, prevention of deterioration, and quality of life, and fewer extrapyramidal symptoms (EPS). However, concerns about EPS have been replaced by concerns about other side effects, such as weight gain, glucose dysregulation and dyslipidemia. These side effects are associated with potential long-term cardiovascular health risks, decreased medication adherence, and may eventually lead to clinical deterioration. Despite a greater understanding of the biochemical effects of these drugs in recent years, the pharmacological mechanisms underlying their various therapeutic properties and related side effects remain unclear. Besides dopamine D 2 receptor antagonism, a characteristic feature of all atypical antipsychotic drugs, these agents also bind to a range of non-dopaminergic targets, including serotonin, glutamate, histamine, a-adrenergic and muscarinic receptors. This review examines the potential contribution of different receptors to metabolic side effects associated with atypical antipsychotic treatment for all seven agents currently marketed in the United States (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone and clozapine) and another agent (bifeprunox) in clinical development at the time of this publication.

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“…Paroxetine increased serum 5-HT levels through inhibiting the reuptake of 5-HT by these cells. Several reports have demonstrated that 5-HT affects insulin secretion via 5-HT receptors [30,42,43] . Our study showed that unlike intracellular 5-HT, extracellular 5-HT inhibited rather than stimulated insulin secretion, which was in an agreement with previous reports [37] .…”

Section: Discussionmentioning

confidence: 99%

Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure

Zhang

et al. 2014

Acta Pharmacol Sin

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Aim: Clinical evidence shows that co-administration of pravastatin and paroxetine deregulates glucose homeostasis in diabetic patients. The aim of this study was to verify this phenomenon in diabetic rats and to elucidate the underlying mechanisms. Methods: Diabetes mellitus was induced in male SD rats by a high-fat diet combined with a low-dose streptozotocin injection. The rats were orally administered paroxetine (10 mg/kg) and pravastatin (10 mg/d) or both the drugs daily for 28 d. The pharmacokinetics of paroxetine and pravastatin were examined on d 1 and d 28. Biochemical parameters including serum insulin, glucose and lipids were monitored during the treatments. An insulin-secreting cell line (INS-1) was used for measuring insulin secretion. Results: In diabetic rats, co-administration of paroxetine and pravastatin markedly increased the concentrations of both the drugs compared with administration of each drug alone. Furthermore, co-administration severely impaired glucose homeostasis in diabetic rats, as demonstrated by significantly increased serum glucose level, decreased serum and pancreatic insulin levels, and decreased pancreatic Insulin-2 mRNA and tryptophan hydroxylase-1 (Tph-1) mRNA levels. Treatment of INS-1 cells with paroxetine (5 and 10 μmol/L) significantly inhibited insulin secretion, decreased the intracellular insulin, 5-HT, Insulin-2 mRNA and Tph-1 mRNA levels. Treatment of the cells with pravastatin (10 μmol/L) significantly stimulated insulin secretion, which was weakened by co-treatment with paroxetine. Conclusion: Paroxetine inhibits insulin secretion at least via decreasing intracellular 5-HT and insulin biosynthesis. The deregulation of glucose homeostasis by co-administration of paroxetine and pravastatin in diabetic rats can be attributed to enhanced paroxetine exposure.

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Antagonism of the Serotonin (5-HT)-2 Receptor and Insulin Sensitivity: Implications for Atypical Antipsychotics

Abstract: The selective 5-HT2 antagonist ketanserin impaired insulin sensitivity. This effect was possibly mediated by suppression of 5-HT(2A) receptor mediated glucose uptake in skeletal muscle.

Cited by 46 publications

References 23 publications

Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes

Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure

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